Benzimidazole derivates useful as inhibitors of mammalian histone deacetylase activity
a technology of benzimidazole and inhibitors, applied in the field of novel, can solve the problems of large risk of significant negative impact on cardiac function, tumor and metastasis,
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example 1
2-(3-Chlorophenyl)-N-hydroxy-1H-benzimidazole-6-carboxamide
General Procedure A
[0394]A solution of 3,4-diaminobenzoic acid (15.2 mg, 0.100 mmol) and p-TSA (3.8 mg, 0.020 mmol) in DMF (1 mL) was heated at 80° C. To the mixture was added 3-chlorobenzaldehyde (11 μL, 0.100 mmol) in DMF (0.4 mL) in 4 portions, with ca. 1 h between each addition. After additional 1 h of stirring at 80° C., most of the DMF was removed on a rotary evaporator and then 1 M NaOH was added (1.5 ml, 1.5 mmol). To facilitate precipitation the pH was adjusted to 5-6 using 6 M HCl and 6 M NaOH. The mixture was centrifuged (3000 rpm, 5 min) and the supernatant was removed. The pellet was washed twice with water and then dried in vacuum giving 2-(3-chlorophenyl)-1H-benzimidazole-6-carboxylic acid in 98% yield (26.7 mg, 99% purity) which was used without further purification. 1H NMR (600 MHz, CD3OD) δ ppm 7.55-7.59 (m, 2H) 7.67 (d, J=8.39 Hz, 1H) 8.00 (dd, J=8.39, 1.53 Hz, 1H) 8.03-8.08 (m, 1H) 8.16-8.18 (m, 1H) 8.34 ...
example 20
2-[4-(Acetylamino)phenyl]-N-hydroxy-1H-benzimidazole-6-carboxamide
General Procedure B
[0396]3,4-Diaminobenzoic acid (15 mg, 0.10 mmol) and methanesulfonic acid (2 mg, 0.02 mmol) were mixed in 500 μl of DMF. The mixture was stirred at 90° C. in an open to air vial. 4-Acetamidobenzaldehyde (0.075 mmol) in DMF (500 μl) was added in portions of 50 μl over 2 h. The reaction mixture was stirred for an additional 3 h and purified with reversed phase chromatography (ACE C8, 5 μm, 21×100 mm, flow 25 ml / min, gradient: water+0.1% TFA / acetonitrile over 12 minutes). The pure fractions were concentrated and dried in vacuum. The intermediate from above was dissolved in acetonitrile (500 μl) and triethylamine (15 mg, 0.15 mmol) and propylphosphonic anhydride (50% in EtOAc, 64 μl, 0.10 mmol) were added. After 30 minutes O-(tetrahydropyran-2-yl)-hydroxylamine (18 mg, 0.15 mmol) was added. The reaction mixture was stirred at 50° C. for 2 h. TFA (1 M, 300 μl) was added. After 2 h at 50° C. the deprotect...
example 80
2-(4-Ethynylphenyl)-N-hydroxy-1H-benzimidazole-6-carboxamide
General Procedure C
[0397]3,4-Diamino-N-hydroxybenzamide, INTERMEDIATE 1 (8 mg, 0.050 mmol) and methanesulfonic acid (0.5 mg, 0.005 mmol) were mixed in 500 μl of DMF. The mixture was stirred at 50° C. in an open to air vial. 4-Ethynylbenzaldehyde (0.050 mmol) in 200 μl of DMF was added in portions of 20 μl over 2 h. The reaction mixture was stirred overnight and purified with reversed phase chromatography (Kinetex C18, 5 μm, 21×100 mm, flow 25 ml / min, gradient: water+0.1% TFA / acetonitrile over 15 minutes). The title compound was obtained after concentration of the pure fractions.
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